The overall goal of the proposed studies is to define targets for endocrine based preventative and/or therapeutic treatments in lung cancer. Epidemiological data indicate that there are sex differences in non-small cell lung cancer and that ovarian hormones play a role by promoting tumor growth, particularly in adenocarcinoma. Tumor promoter action of hormones is likely to be most effective early in the carcinogenic process. For that reason, studies aimed at development of endocrine-based chemopreventive measures are best studied in controlled, inducible animal models. Using a unique murine model of lung adenocarcinoma based on the conditional expression of oncogenic KRAS (KRasG12D) and concurrent deletion of Tp53, we have found that females develop more tumors and higher grade tumors than males. Ovariectomy abrogates these sex differences and estrogen treatment restores tumor number but not tumor grade, indicating that another ovarian factor is involved in tumor progression. Considering the interplay between estrogen and progesterone in cancers of other organs, it is likely that progesterone is the ovarian tumor progression factor. Thus, receptors for ovarian steroids are logical targets for intervention. There are three known receptor proteins for estrogen, the nuclear ligand-activated transcription factors, ER? and ER?, and the membrane G-protein coupled receptor, GPER. Lung cells express all three of the estrogen receptors;they also express progesterone receptor (PR), another nuclear, ligand activated transcription factor. Our preliminary observations indicate that the widely used antiestrogens, tamoxifen and fulvestrant, behave as agonists, promoting tumorigenesis in the mouse lung cancer model;these two antiestrogens interact with all three receptor types, producing either agonist or antagonist action, depending on the tissue and the physiological process being examined. Hence, it is necessary to define the pathway(s) involved in estrogen promotion of lung tumors before designing targeted therapies. Using three receptor specific compounds proven effective in other organs systems, we will determine which of the three estrogen receptor types mediate the tumor promoter action of estrogens. In this way we can identify the precise target(s) for future development of antiestrogens that can be used against lung cancer. On the other hand, using the antiprogestin, mifepristone, we will determine the role of PR in tumor progression. In addition to assessing the effects of treatments on tumorigenesis, we will examine intermediate end points relevant to the process. We will determine the rate of cell proliferation and apoptosis in preneoplastic cells and we will assess expression of several genes known to be responsive to estrogens through distinct molecular pathways. In this way we will correlate the effect of treatment on tumorigenesis and cellular processes that lead to tumor development. These minimal studies will pave the way for testing receptor specific estrogen antagonists and additional PR-specific antagonists in prevention of tumor growth and progression in the lung. PUBLIC HEALTH RELEVANCE: Lung cancer differs between men and women, most likely due to the effects of ovarian hormones. Definition of the basic mechanisms involved in establishing sex differences in lung cancer is a prerequisite to rational design of novel endocrine-based preventative measures and/or therapies.